Rational design of 4-aryl-1,2,3-triazoles for indoleamine 2,3-dioxygenase 1 inhibition.
(2012) Journal of Medicinal Chemistry — Vol. 55, n° 11, p. 5270-5290 (2012)
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- Indoleamine 2,3-dioxygenase 1 (IDO1) is an important therapeutic target for the treatment of diseases such as cancer that involve pathological immune escape. Starting from the scaffold of our previously discovered IDO1 inhibitor 4-phenyl-1,2,3-triazole, we used computational structure-based methods to design more potent ligands. This approach yielded highly efficient low molecular weight inhibitors, the most active being of nanomolar potency both in an enzymatic and in a cellular assay, while showing no cellular toxicity and a high selectivity for IDO1 over tryptophan 2,3-dioxygenase (TDO). A quantitative structure-activity relationship based on the electrostatic ligand-protein interactions in the docked binding modes and on the quantum chemically derived charges of the triazole ring demonstrated a good explanatory power for the observed activities.
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Röhrig, U. F., Majjigapu, S. R., Grosdidier, A., Bron, S., Stroobant, V., Pilotte, L., Colau, D., Vogel, P., Van den Eynde, B., Zoete, V., & Michielin, O. (2012). Rational design of 4-aryl-1,2,3-triazoles for indoleamine 2,3-dioxygenase 1 inhibition. Journal of Medicinal Chemistry, 55(11), 5270-5290. https://doi.org/10.1021/jm300260v (Original work published 2012)